tbuckley/cabot-search huggingface dataset:
RONC-07. Fractionated radiotherapy is required to accurately mimic neurostructural late effects in preclinical models
Authors: Jacqueline Whitehouse, Meegan Howlett, Jessica Buck, Kale Somers, Jessica Lawler, Hilary Hii, Brooke Carline, Mani Kuchibhotla, Bhedita Sewoo, Tim Rosenow, Kirk Feindel, Martin Ebert, Andrew Mehnert, Nicholas Gottardo, Raelene Endersby
Journal: Neuro-Oncology (2022)

Abstract Pediatric brain cancer patients treated with fractionated radiotherapy commonly develop long-term late side-effects including cognitive deficits. Many preclinical models of late effects have been developed that use a single, high dose of radiotherapy, which does not mimic the fractionated schedule children receive clinically. This study aimed to create a mouse model of late effects using clinically-relevant fractionated radiotherapy, and to measure the effects on the developing brain. Juvenile mice were treated at postnatal day 16 with a single dose of 8Gy whole brain radiation, or a mathematically-equivalent fractionated dose of 18Gy (9 x 2Gy daily fractions). Sham control mice received a CT scan, or 9 x sham CT scans. Mice were allowed to grow to young adulthood (63 days). Ex vivo anatomical MRI scans were performed along with diffusion tensor imaging (DTI) and histology. Mice receiving a single 8Gy radiation dose exhibited significantly decreased volumes in areas including the olfactory bulbs (-19%), hippocampus (-7%), corpus callosum (-9%) and motor cortex (-9%). In contrast, mice receiving fractionated radiotherapy showed fewer significantly decreased regions, although olfactory bulbs were reduced (-12%). Furthermore, doublecortin-positive cells were significantly reduced in the dentate gyrus indicating profound effects of radiotherapy on murine neural stem cells. Few radiotherapy-induced differences were observed by DTI, and immunohistochemistry revealed no changes in myelin basic protein, suggesting that white matter is minimally altered in mice. These results show that preclinical models exhibit treatment-induced late effects, and that commonly-used experimental approaches of single dose radiotherapy induce more neurological changes than an equivalent fractionated dose, thus may over-estimate radiotherapy-induced late effects. We have developed a clinically-relevant fractionated dosing protocol in mice, which replicates late effects experienced by children, and can be used to measure long-term effects of novel chemo/radiotherapy treatment combinations, ensuring children with brain cancer receive treatment both effective and safe treatment.
Prognostic value of circulation tumor DNA dosing in patients in neoadjuvant breast neoplasia (GIRO-ctDNA).
Authors: Camila Giro, Felipe Melo Cruz, Lilian Arruda De Rêgo Barros, Fernando Luiz Affonso Fonseca, Auro Del Giglio, Alayne Magalhaes Trindade Domingues Yamada
Journal: Journal of Clinical Oncology (2022)

e12559 Background: Pathologic Complete Response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer is strongly associated with a favorable prognosis. We evaluated whether there is a correlation between serum levels of circulating tumor DNA (ctDNA) during neoadjuvant therapy with obtaining pCR and detection of residual disease after treatment. Methods: ctDNA was isolated from 310 plasma samples of 27 patients diagnosed with localized and/or locally advanced breast cancer treated with standard NAC alone or combined with immunotherapy and/or anti-HER 2- targeted therapy when indicated. Blood was collected at pretreatment, every 15 days during treatment and before surgery. Results: Eight (29%) of the 27 patients presented pCR, 4 triple negative (50%, 3 HER2+ (37%) and 1 (13%) luminal B. We observed that throughout the neoadjuvant treatment in the seventh collection the ctDNA levels were significantly higher in patients who did not presented pCR in relation to those who achieved it, p-value = 0.014. 62% of patients who presented pCR in the surgical specimen also had a complete radiological response, with a significant correlation, p-value = 0.02492. Although we did not find statistical significance, we did note that patients who presented pCR had a tendency towards an initial increase in their ctDNA levels after the first cycle of chemotherapy. Conclusions: ctDNA dosage in the third month (seventh collection) of neoadjuvant treatment is inversely correlated with the achievement of tumor pCR. The tendency we saw of an increased ctDNA levels soon after the initiation neoadjuvant chemotherapy could indicate tumor sensitivity by the increase in cell death with release of ctDNA into the circulation. Clinical trial information: NCT05050890.
Cabozantinib (C) plus atezolizumab (A) or C alone in patients (pts) with advanced non–small cell lung cancer (aNSCLC) previously treated with an immune checkpoint inhibitor (ICI): Results from Cohorts 7 and 20 of the COSMIC-021 study.
Authors: Joel W. Neal, Armando Santoro, Santiago Viteri, Santiago Ponce Aix, Bruno Fang, Farah Louise Lim, Ryan D. Gentzler, Jerome H. Goldschmidt, Polina Khrizman, Erminia Massarelli, Shiven B. Patel, Sonam Puri, Ramu Sudhagoni, Christian Scheffold, Dominic Curran, Enriqueta Felip
Journal: Journal of Clinical Oncology (2022)

9005 Background: C, a multitargeted receptor tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment that may enhance ICI activity. COSMIC-021 (NCT03170960) is a multicenter phase 1b study evaluating C + A in advanced solid tumors. In COSMIC-021, C + A demonstrated encouraging clinical activity in the cohort of pts with aNSCLC previously treated with ICIs (cohort 7 [C7]) (Neal. ASCO 2020. Abstr 9610). Updated outcomes of C + A in expanded C7 and outcomes for C alone in exploratory cohort 20 (C20) are presented. Methods: Pts with stage IV nonsquamous NSCLC without mutations in EGFR, ALK, ROS1, or BRAF V600E who progressed on one prior ICI and ≤2 prior lines of systemic anticancer therapy but no prior VEGFR TKI were eligible. Cohorts were not accrued contemporaneously. Pts received C 40 mg PO QD plus A 1200 mg IV Q3W (C7) or C alone 60 mg PO QD (C20). Primary endpoint was objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). CT/MRI scans were performed Q6W for the first year and Q12W thereafter. Results: A total of 81 and 31 pts received C + A and C, respectively; baseline characteristics were as follows: median age, 67 y, 70 y; male, 57%, 58%; ECOG PS 1, 64%, 71%; liver metastasis, 21%, 23%; refractory to prior ICI (progressive disease [PD] as best response), 32%, 45%; median number of prior systemic therapies, 3 and 3. As of Nov 30, 2021, median follow-up (range) (mo) was 24.7 (10.7, 42.8) and 21.5 (17.3, 27.6) for C + A and C, respectively, with 6 (7%) and 1 (3%) on study treatment. Clinical activity was observed for C + A and C alone (Table). Most common treatment-related adverse events (TRAEs) of any grade for C + A and C, respectively, included diarrhea (40%, 42%), nausea (22%, 45%), decreased appetite (25%, 26%), vomiting (14%, 23%), and fatigue (28%, 19%); grade 3/4 TRAEs occurred in 44% and 52% and one grade 5 TRAE occurred in each cohort (pneumonitis [C + A] and gastric ulcer hemorrhage [C]). Conclusions: C + A and C demonstrated encouraging clinical activity with manageable toxicity in pts with aNSCLC previously treated with ICIs. A phase 3 trial (CONTACT-01; NCT04471428) of C + A vs docetaxel is ongoing in NSCLC previously treated with an ICI and platinum-containing chemotherapy. Clinical trial information: NCT03170960. [Table: see text]
A Cancer Cell Membrane‐Derived Biomimetic Nanocarrier for Synergistic Photothermal/Gene Therapy by Efficient Delivery of CRISPR/Cas9 and Gold Nanorods
Authors: Lin Huang, Mengyang Zhou, Ghulam Abbas, Chao Li, Mengmeng Cui, Xian‐En Zhang, Dian‐Bing Wang
Journal: Advanced Healthcare Materials (2022)

Abstract Bimodal synergistic therapy produces superadditive effect for enhanced therapeutic efficacy. However, how to efficiently and simultaneously deliver several kinds of therapeutic agents is still challenging. A cancer cell membrane‐derived nanocarrier (mCas9‐sGNRs) is proposed for synergistic photothermal/gene therapy (PTT/GT) by efficient delivery of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR‐associated protein 9 (Cas9) and gold nanorods (GNRs). In this approach, Cas9 proteins can be efficiently loaded inside the cell membranes (mCas9) by electrostatic interactions. Similarly, single‐guide RNAs, which target survivin, can be loaded onto GNRs (sGNRs) through electrostatic interactions and encapsulated by mCas9. As a result, the nanodelivery systems present advantages in biocompatibility, homologous targeting capacity and loading efficiency of cargoes. In addition, significant antitumor effects is achieved by gene editing of survivin which induces anticancer activity and reduces heat tolerance of cancer cells caused by GNRs mediated PTT due to the downregulation of HSP70. These results indicate the nanotherapeutic platform leads to enhanced PTT/GT efficacy. Therefore, this work not only provides a general strategy to construct a versatile nanoplatform for loading and target delivery of several therapeutic cargos but will also be valuable for PTT/GT and other bimodal synergistic therapy.
Phase 2 study of tarlatamab, a DLL3-targeting, half life–extended, bispecific T-cell engager (HLE BiTE)immuno-oncology therapy, in relapsed/refractory small cell lung cancer (SCLC).
Authors: Suresh S. Ramalingam, Myung-Ju Ahn, Hiroaki Akamatsu, Fiona Helen Blackhall, Hossein Borghaei, Horst-Dieter Hummel, Melissa Lynne Johnson, Martin Reck, Yiran Zhang, Danielle Jandial, Sunfa Cheng, Luis G. Paz-Ares
Journal: Journal of Clinical Oncology (2022)

TPS8603 Background: SCLC is characterized by rapid growth and early development of metastases. Platinum-based first-line chemotherapy is associated with a high initial response rate; however, disease recurrence is common. Delta-like ligand 3 (DLL3) is a Notch ligand that is upregulated and aberrantly expressed on the cell surface in most SCLC, making it a compelling therapeutic target. Tarlatamab is an HLE BiTE immuno-oncology therapy designed to bind DLL3 on target cancer cells and CD3 on T cells, forming a cytolytic synapse inducing T cell activation and expansion and T cell-dependent killing of tumor cells. Interim results of an ongoing first-in-human study in patients with relapsed/refractory SCLC (NCT03319940) show preliminary evidence for tarlatamab efficacy in pretreated patients with confirmed partial responses in 20% of patients and duration of response of 8.7 months (Owonikoko TK, et al. Abstract 8510. Presented at: ASCO Annual Meeting, June 4–8, 2021; Virtual). Grade ≥ 3 treatment-related AEs (TRAEs) occurred in 27% of patients and TRAEs resulted in discontinuation in 5% of patients. This promising efficacy/safety profile supports further study of tarlatamab in SCLC. Methods: NCT05060016 is a phase 2, open-label study evaluating tarlatamab in patients with relapsed/refractory SCLC after two or more lines of prior treatment. Part 1 is a dose characterization phase in which subjects will be randomized 1:1 to two active doses of tarlatamab. Part 2 will continue enrollment for the selected target dose only based on interim analysis of Part 1. Key eligibility criteria include adults with histologically or cytologically confirmed SCLC whose disease progressed/recurred after two or more lines of prior treatment including at least 1 platinum-based regimen (including a PD-L1 inhibitor, if standard of care, with certain exceptions per protocol), treated brain metastases, ECOG performance status ≤1, and life expectancy ≥ 12 weeks in the opinion of the investigator. The primary endpoint for the primary analysis is ORR per RECIST 1.1 as assessed by blinded independent central review. Secondary objectives are to evaluate antitumor activity by additional measures (duration of response, progression-free survival, disease control rate and duration, overall survival), safety and tolerability, immunogenicity, and pharmacokinetics. Sites in North America, Asia and Europe are participating in the trial with subjects already enrolled and enrollment ongoing. Clinical trial information: NCT05060016.
Describing U.S. real-world patients (pts) with hormone receptor-positive early breast cancer (HR+ EBC) by risk status.
Authors: Mary K. Downer, Amin Yakubu, Pablo Diego Pérez-Moreno, Anna Steenrod, Tanja Badovinac Crnjevic, Zuzana Machackova
Journal: Journal of Clinical Oncology (2022)

e12548 Background: Despite high endocrine therapy (ET) efficacy in HR+ EBC, there is an unmet need to improve outcomes across risk statuses. We describe HR+ EBC demographic and tumor characteristics, treatment, and outcomes by risk status, to inform trial design, outcomes, and care. Methods: Pts from the de-identified, nationwide US, Flatiron Health electronic health record-derived database had HR+ EBC diagnosed from January 1, 2011 to November 30, 2020. We grouped pts into EBC with clinically relevant, high risk (stage T4 or ≥N2; or N1 with ≥1 of ≥T3, grade 3, Ki67 ≥20%, Oncotype DX ≥26), medium risk (N1, not high risk; or N0 with ≥1 of grade 3, Ki67 ≥20%, Oncotype DX ≥26), or low risk (N0, not medium risk) of recurrence. Chi-square and Kruskal–Wallis tests compared characteristics and treatments; Kaplan–Meier methods estimated event-free/overall survival (EFS/OS). Results: Of 7924 pts, 3908 (49.3%), 2477 (31.3%), and 1213 (15.3%) were classified as low-, medium-, and high-risk EBC, respectively (326 missing). Pts with medium-/high-risk EBC vs low-risk were less likely to be non-Hispanic white (p &lt; 0.001), more likely to receive BRCA, MammaPrint, or next-generation sequencing testing (p &lt; 0.001), be slightly younger (p &lt; 0.001), pre-menopausal at diagnosis (p &lt; 0.001), diagnosed in earlier calendar years (p = 0.01), and have invasive lobular carcinoma (p &lt; 0.001). Pts with high-risk EBC were more likely to receive neoadjuvant chemotherapy (NACT) ± ACT vs lower risk. High-risk EBC had significantly lower 3-year EFS/OS vs medium-/low-risk (EFS 0.85 [95% CI = 0.82, 0.87] vs 0.95 [0.94, 0.96]/0.98 [0.98, 0.99], p &lt; 0.0001; OS 0.9 [0.88, 0.92] vs 0.97 [0.96, 0.97]/0.97 [0.96, 0.97], p &lt; 0.0001). Conclusions: Real-world differences in US characteristics, treatments, and outcomes by risk status exist in HR+ EBC. As expected, pts with higher risk EBC were more likely to receive NACT ± ACT. Despite missing risk factors and limited follow-up, and potential misclassification of risk status/treatment and overestimation of time-to-events, US treatment patterns are guideline-aligned. Inferior outcomes in high-risk HR+ EBC show a continued need for improved treatments.[Table: see text]
HGG-22. Uptake of investigational therapy in children with High Grade Glioma
Authors: Helen Toledano, Abed Abu-Quider, Walid Kaddan, Suzanna Fichman-Horn, Amir Kershenovich, Orli Michaeli
Journal: Neuro-Oncology (2022)

Abstract High grade gliomas (HGG) in children carry a dismal prognosis. Standard therapy includes resection when possible, radiotherapy and sometimes the addition of temozolomide. There is no standard treatment for progression or relapse. Since November 2018 we have offered upfront molecular testing to all children with HGG who had biopsy/ resection. Testing was mainly done by next generation sequencing panel, and some had research based methylation profiling and RNA seq. We aimed to see whether families chose to receive additional investigational treatment as a result of the molecular testing results and whether the treatment involved participation in a clinical study, or whether treatment was compassionate. A total of 22 patients aged 2.8-16.8 years with HGG had a biopsy/resection over this three year period. Thirteen had diffuse midline glioma (DMG) of which 11 had the H3K27 mutation, and 9 were cortical. Six children had underlying predisposition syndromes: mismatch repair deficiency (n=3 proven + 1 highly suspected), neurofibromatosis1 (n=1), Li-Fraumeni (n=1). All the cortical gliomas had potential treatment options based on their molecular testing. 10/22 (45%) children received investigational therapy of which only three participated in a clinical study while the rest received compassionate therapy. Compassionate treatments included BRAF/MEK inhibitors (n=4), Larotrectinib (n=1), and immune checkpoint inhibitors (n=2). Of the 12 who did not receive investigational therapy, four, all cortical, have potential therapy options but are currently in remission. Of the remaining eight, two had very rapid clinical deterioration and died, and six (all DMG) did not wish/ were unable to travel abroad and no relevant clinical study was available locally. We conclude that the families of children with HGG are highly motivated to receive investigational therapy. Upfront molecular testing of these tumors, especially for cortical HGG, is imperative and there is a growing need for accessible clinical studies.
Phage display of environmental protein toxins and virulence factors reveals the prevalence, persistence, and genetics of antibody responses
Authors: Julia W. Angkeow, Daniel R. Monaco, Athena Chen, Thiagarajan Venkataraman, Sahana Jayaraman, Cristian Valencia, Brandon M. Sie, Thomas Liechti, Payam N. Farhadi, Gabriela Funez-dePagnier, Cheryl A. Sherman-Baust, May Q. Wong, Ingo Ruczinski, Patrizio Caturegli, Cynthia L. Sears, Patricia J. Simner, June L. Round, Priya Duggal, Uri Laserson, Theodore S. Steiner, Ranjan Sen, Thomas E. Lloyd, Mario Roederer, Andrew L. Mammen, Randy S. Longman, Lisa G. Rider, H. Benjamin Larman
Journal: Immunity (2022)
A nationwide study on the added value of (neo)adjuvant ADT in addition to modern dose-escalated external beam radiotherapy in men with high-risk localized prostate cancer
Authors: B.L. Heesterman, K.K.H. Aben, C.G.J.I. Van Straten, J.R.N. Van Der Voort Van Zyp, L.P. Bokhorst
Journal: European Urology (2022)
MEDB-84. The French experience of ELP1-related medulloblastomas
Authors: Arnault Tauziède-Espariat, Léa Guerrini-Rousseau, Alexandre Perrier, Jacob Torrejon, Flavia Bernardi, Mathilde Filser, Pascale Varlet, Emilie De Carli, Anne Pagnier, Pierre Leblond, Cécile Faure-Conter, Francois Doz, Anne-Isabelle Bertozzi, Ludovic Mansuy, Marjolaine Willems, Gilles Palenzuela, Natacha Entz-Werle, Christine Bourneix, Lauren Hasty, Olivier Delattre, Thomas Blauwblomme, Kevin Beccaria, Alice Metais, Olivier Ayrault, Fabrice Chrétien, Franck Bourdeaut, Christelle Dufour, Julien Masliah-Planchon
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB), the most frequent embryonic tumor of the cerebellum is classified into four molecular subgroups (WNT group, SHH group, group 3 and group 4). Although the vast majority of MB are sporadic, predisposing genetic diseases have been described in rare WNT MB and more frequently in the SHH group. In a recent pediatric series of SHH-MB, germline alterations of the ELP1 gene have been described in 14% of cases, making this gene the most frequent genetic predisposition in MB. We have investigated the potential interest of ELP1 immunostaining on a large cohort of 132 MB. A complete loss of ELP1 staining was observed in 12 SHH MB (among 57 total SHH MB: 21%). The loss of ELP1 immunostaining was well correlated with the presence of a bi-allelic alteration of the gene except for one case for which the MB had a loss of ELP1 protein expression demonstrated by immunohistochemistry (IHC) and confirmed by whole proteome analysis, although no obvious genetic alteration in the coding sequence of ELP1 could be found. Molecular analysis of a large “molecular” cohort of 266 MB from French centers for which somatic ELP1 was sequenced allows to identify 12 additional MB with bi-allelic ELP1 genetic alterations. Our results demonstrate the benefit of the ELP1 IHC as an accurate and reliable tool to screen ELP1-deficient MB. This new immunohistochemical tool will now be advantageously used to screen SHH MB upfront for genetic alteration in ELP1, and will subsequently help orientating these patients towards genetic counseling.
Imaging of solid tumors using 68Ga-FAP-2286.
Authors: Thomas A. Hope, Rahul Raj Aggarwal, Mallika Sachdev Dhawan, Robin Kate Kelley, Robert R. Flavell, Courtney Lawhn Heath, Yan Li, Sima P. Porten, Hope S. Rugo, Sue S. Yom, Robin Ippisch, Vadim S Koshkin
Journal: Journal of Clinical Oncology (2022)

3059 Background: Fibroblast Activation Protein (FAP) is a transmembrane protein overexpressed on cancer associated fibroblasts (CAFs), and is abundantly present in many epithelial cancers, suggesting FAP is an attractive imaging and therapeutic target. FAP-2286 is a cyclic peptide that binds to FAP and is currently being evaluated as a radioligand therapy to treat patients (pts) with FAP-positive solid tumors. The role of 68Ga-FAP-2286 as a diagnostic agent is unknown. We present an interim analysis of the ability of 68Ga-FAP-2286 to detect metastatic disease across multiple cancer types. Methods: This is a first in human Phase I/II study of 68Ga-FAP-2286 (NCT04621435) with a planned total enrollment of 65 pts across 3 cohorts: dosimetry cohort (n = 5), cohort with RECIST measurable disease (n = 30) and a cohort at risk for metastases without measurable disease (n = 30). By the cutoff date of February 12, 2022, 27 pts were enrolled (3 in cohort 1, 15 in cohort 2 and 9 in cohort 3). For each pt, the five largest lesions were included for analysis, and for each lesion, the maximum standardized uptake value (SUVmax) of the 68Ga-FAP-2286 and the size (short axis for lymph nodes) were documented. In pts who had an available FDG PET performed within 8 weeks of 68Ga-FAP-2286 PET, uptake on the two scans was compared. Results: Of the 27 enrolled pts, 9 had bladder cancer, 5 sarcoma, 4 head and neck squamous cell cancer (HNSCCA), 3 breast cancer (BC), and 3 castration resistant prostate cancer (CRPC). Most pts (89%, 24/27) had tumors positive for uptake on 68Ga-FAP-2286 PET, including 30 lesions &lt; 1.5 cm, and 17 less than 1.0 cm. 16 pts had a paired FDG PET. In these pts, the average SUVmax on 68Ga-FAP-2286 PET was 244% higher than on FDG PET. Only two pts had higher uptake on FDG PET than on 68Ga-FAP-2286 PET (HNSCCA and DSRCT). The highest relative uptake was seen in 2 pts with BC (both 3.4 times higher on 68Ga-FAP-2286 PET); the average SUVmax in BC was 16.6. The lowest uptake on 68Ga-FAP-2286 PET was CRPC with an average SUVmax of 7.0. Sarcoma had variable uptake with one pt having an SUVmax of 4.5 (Ewing’s), while two pts had an SUVmax over 30 (both undifferentiated pleomorphic). Although sarcoma had high uptake on 68Ga-FAP-2286 PET, it was similar to FDG PET uptake across the 5 pts (ratio to FDG PET = 1.0). Conclusions: 68Ga-FAP-2286 is a promising imaging agent across cancers, although its benefit is not seen equally. BC had the highest absolute uptake and highest relative uptake compared to FDG PET; prostate cancer had the lowest uptake. Further work should be undertaken to define the settings where 68Ga-FAP-2286 PET may inform clinical decision making, and which pts may benefit from FAP-targeted radioligand therapy. Clinical trial information: NCT04621435.